J. P. Vandenbroucke

Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen

Recent concern about the safety of combined oral contraceptives (OCs) with third-generation progestagens prompted an examination of data from a population-based case-control study (Leiden Thrombophilia Study). We compared the risk of deep-vein thrombosis (DVT) during use of the newest OCs, containing a third-generation progestagen, with the risk of older products. We also investigated the influence of family history of thrombosis, previous pregnancy, age, and the thrombogenic factor V Leiden mutation. We selected 126 women with DVT and 159 controls aged 15-49 (mean age 34.9) and premenopausal and found, as compared with non-users, the highest age-adjusted relative risks to be that for an OC containing desogestrel and 30 micrograms ethinyloestradiol (relative risk [RR] 8.7, 95% CI 3.9-19.3). We found lower relative risks for all other types of OC, ranging from 2.2 to 3.8. In a direct comparison, users of the desogestrel-containing oral contraceptive had a 2.5-fold higher risk (95% CI 1.2-5.2) than users of all other OC types combined. The relative risk for the desogestrel-containing OC was similar among women with and without a family history--ie, preferential prescription because of family history cannot explain our findings. Nor could the excess risk be explained by previous pregnancy, and it was highest in the youngest age categories, where we would expect most new users. The age-adjusted RR for the desogestrel-containing contraceptive was 9.2 (3.9-21.4) among non-carriers of the factor V Leiden mutation and 6.0 (1.9-19.0) among carriers of the mutation. This latter risk is superimposed on the 8-fold increased risk of venous thrombosis for carriers of the factor V Leiden mutation. The risk of carriers using the desogestrel-containing OC as compared with noncarrier non-users will therefore be increased almost 50-fold. Use of low-dose OCs with a third-generation progestagen carries a higher risk of DVT than the previous generation of OCs. The absolute risk of DVT associated with these OCs seems to be especially high among carriers of the factor V Leiden mutation and among women with a family history of thrombosis. However, the higher risk associated with OC with a third-generation progestagen compared with previous generations was also present in women without factor V Leiden and with no family history.

Efficacy of antibiotic prophylaxis for prevention of native-valve endocarditis

Whether antibiotic prophylaxis can prevent bacterial endocarditis is hotly debated. In an attempt to settle this issue, we have assessed the efficacy of prophylaxis for bacterial endocarditis on native valves in a nationwide, case-control study in the Netherlands. Cases were patients with known cardiac disease in whom endocarditis developed within 180 days of a medical or dental procedure for which prophylaxis was indicated. Of a total of 438 patients with endocarditis diagnosed during 2 years, 48 were eligible for the study. Controls were patients with the same cardiac status in whom endocarditis did not develop within 180 days of a similar procedure; of a total of 889 controls from five hospitals, 200 were eligible. Overall, about 1 in 6 patients in both groups had received prophylaxis. The best estimate of protective efficacy was 49% for first-ever endocarditis occurring within 30 days of a procedure. Endocarditis developed within 30 days of a procedure in only 13% of patients with a previously diagnosed heart lesion which predisposed to the disease. The findings suggest that strict adherence to generally accepted recommendations for prophylaxis might do little to decrease the total number of patients with endocarditis in the community.

Prophylaxis for endocarditis.

For a long time it has been known that bacteraemias caused by medical or dental procedures may cause endocarditis in patients with specific types of congenital or acquired heart disease. In the 1940s it was thought that the administration of antibiotics before such procedures would prevent endocarditis. However, the beneficial effect of this preventive measure on the incidence of endocarditis did not live up to its expectations. Quite soon it became obvious that prophylaxis was not 100% efficacious in man, although it did prevent endocarditis in animals. A controlled study into the protective effect of prophylaxis in humans has never been carried out. In the last decade it has become dear from case-control studies that endocarditis prophylaxis is not a very effective preventive measure but that it reduces an already small risk even further. In this article the theoretical background of endocarditis prophylaxis and possible explanations for its lack of effect are discussed.